16alpha-methyl-17alpha-hydroxy-delta9-pregnene-3, 20-dione and process for manufacture



Unit d States Patent iiiif'alii the invention is prepared by oxidationof 16oz-Inethyl-3a, 2,970,155 l7a-dihydroxy-A -pregnene-20-oneillustrated as follows:

16a-METHYL-17a-HYDROXY A PREGNENE-3,20- DIONE AND PROCESS FORMANUFACTURE t f 0 $3 Robert Joly, Montmorency, Julien Warnant,Neuilly-surv T Seine, and Leon Velluz, Paris, France, assignors to Les Vl Laboratoires Francais de Chimiotherapie, Paris, -CH3 "CH: France, acorporation of France i No Drawing Filed May 12, 1960, Ser. No. 28,543

- I II Claims priority, application France May 15, 1959 sIclaims. c1.260397.45)

The starting material (I) is obtained by the method The presentinvention relates to a novel methylated disclosed in the copendmgcommonly'asslgned Patent pregnane ketone and thg process for itsproduction appl cation Serial No. 862,491, filed December 29, 1959,

More particularly, it relates to the production of the startfng- Wlthl6u-rilethyl-3afl7M-dIhYQYOXY-PYEgHaHe-I novel compound 16 h 147 h d 9 320-dione by format on of the 20 semicarbazone, reduc- 20 dine f the fla: tion of the latter with potassium borohydride, regenera- 20 tion ofthe ketone function in the 20-position by pyruvic E acid exchange anddehydration in the 9,1l-position through the ll-mesylate intermediate(ll-methane sulfonate ester).

According to the preferred mode of operation of the process of thepresent invention, chromic acid is dissolved at a low temperature inpyridine, a pyridine solution of l6a-methyl-3a,l7a-dihydroxy-A-pregnene-20-one 0 (I) is added thereto, the mixture is agitated,l6a-methyl-17m-hydroxy-A -pregnene-3,ZO-dione (lI) formed thereby isprecipitated out, and the latter :is isolated by extraction in anappropriate solvent, such as chloroform.

The following example is provided to illustrate our invention andenables persons skilled in the art to practice the invention without,however, limiting it. The melting points recited in the example havebeen determined on a Maquenne block.

which is a physiologically-active product and can, moreover, he used asthe intermediate in the preparation of other physiologically-activederivatives of the l6a-methyl-pregnane series. For example, the said16a-methyl- 17a-hydroxy-A -pregnene-3,ZO-dione can be brominated in the2,4-position, dehydrobrominated according to the known processes,acetoxylated in the 21-position according to the process described inthe copending commonly- EXAMPLE assigned patent application Serial No.3,514, filed Janu- 9 ary 20, 1960, now abandoned, and16a-methyl-9a-fluoro- Preparatw of prednisolone acetate or Dexamethasonecan finally be 40 pregnene'3'zo'dmne Qbtained, according to known P At atemperature below 10 C., 2 gm. of chromic acid The series of operationsdescribed above are shown in are dissolved in 20 cc. of pyridine, thetemperature is the following schematic reaction equation below. allowedto rise to 15 C. and then a solution of 2 gm. of

Hg (RH! =0 0:0

W3 1: Br ijl .QU 1gp oi; wit. 1; .QU 1m l An object of this invention isthe obtention of 16m 16m-methyl-3a,l7a-dihydroxy-A -pregnene-ZO-one in20 methyl-17a'hydroxy-A -pregnene-il,ZO-dione. cc. of pyridine is addedthereto. The solution is agitated A further object is to provide aprocess for producing at room temperature for 46 hours, the isolubleportion is 16a-methyl-17a-hydroxy-A -pregnene-3,ZO-dione. separated byvacuum filtration, it is extracted with chloro- These and other objectsof our invention will become formand a mixture of gm. of crushed ice and100 cc.

' apparent as the description thereof proceeds. of water are added tothe pyridine solution. The mix- The16a-methyl-17a-hydroxy-A-pregnene-3,20-dione of ture is agitated and vacuum filtered. The filtercake is arecombined, washed with water, 11.16 1 ih J N sulfuric acid andagain with water, dried on sodium sulfate and evaporated to dryness innitrogen.

0 1.560 gm, that is, a'yield of 78.4% of 1-60t-mthy1- I7'ix-hydroxy-A-pregnene-3,ZO-dione, melting point: 198 C., specific rotation [a] =+22.5- 1 (c.=0.5% acetone),'are obtained.

The product, which has not been previously known, is obtian'ed in theform of small colorless crystals, insoluble in water and ether, slightlysoluble in alcohol and acetone, and soluble in benzene and chloroform,

Analysis.- C H O #34448.-Calculated: C, 76.7%; H, 9.36%. Found. C,76.9%; H; 9.3%.

While we haveset forth a specific example and-pie. ferred modeofpractice of our invention, it will be tinderstood that the 'inventionis not limited thereto and that various changes 'andn-iodificationsmay-be made in'"the A-pregnene-3,20-dione which comprises oxidizing16amethyl-3a,l7a-dihydroxy-A -pregnene-20-one.

3. A process for producing l6a-methyl-l7bt-hydroxy A-pregnene-3,20-dione which comprises oxidizing16ccmethyl-3u,17u-dihydroxy-A -pregnene-20-one with chromic acid. 1

4. A process for producing 16a-methyl-17a-hydroxy- A-pregnene-3,20-dione which comprises dissolving chro-i mic acid inpyridine, reacting a pyridine solution of 16ainvention without departing"from the spirit of'the dis! closure and 'the' scope offtheappendedclaims;

Weclaim: j 1. 1Got-methyl-17u-hydroxy-A -pregnene-3,20-dione.

2. A process for producing16a-methyl-17u-hydroxymethyl-301,17wdihydroXy-A -pregnene-ZO-one withsaid chromic acid solution, precipitating l6u-methyl-17a-hy-' droxy-A-pregnene-3,20-di0ne, and extracting said precipitate with an organicsolvent.

5. A process for producing l6u-methyl-17 -hydroxy- A-pregnene-3,20-dione which comprises dissolving chromic acid in"pyridine at low temperature, adding'a-pyridine solution ofl6a-methyl-3a,17a-dihydroxy-A -pregnene-ZO-one to said chromic acidsolution and agitating at room temperature, precipitatinglfia-methyl-flqz-hydroxy-A -pregnene-3,20-dione, and extracting saidpiecipitate with chloroform. f i

No references cited.

UNITED STATES PATENT OFFICE CERTIFICATION OF CORRECTION Patent No. 29?O,l55 January 31, 1961 Robert Joly et al.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said 'Letters Patent should read ascorrected below.

Column 2, lines 3 to 13 Formula I should appear as shown below insteadof as in the patent: (1H

column 2, line 68, for "isoluble" read insoluble column 3 line 10 for"obtianed" read obtained Signed aim sealed this lst day of August196510;,

(SEAL) Attest:

ERNEST W. SWIDER DAVID L. LADD Attesting Officer Commissioner of Patents

1. 16A-METHYL-17A-HYDROXY-$9-PREGNENE-3,20-DIONE.
 3. A PROCESS FORPRODUCING 16A-METHYL-17A-HYDROXY$9-PREGNENE-3,20-DIONE WHICH COMPRISESOXIDIZING 16AMETHYL-3A,17A-DIHYDROXY-$9-PREGNENE-20-ONE WITH CHROMICACID.